Project Summary The increased risk of Alzheimer?s Disease (AD) in women compared to men has been widely reported, including increased prevalence and also severity of cognitive impairment in women with AD than men. Women also exhibit an accelerated rate of impairment. However, there is considerable debate as to the physiological basis for this increased susceptibility. One potential key candidate mechanism that may underlie this vulnerability is differences in synaptic structure and function. To examine this question, we have opted to utilize a preclinical mouse model that exhibits endophenotypes of AD as well as normal aging mice. In particular, the familial AD 5xFAD transgenic mouse model recapitulates many AD characteristics, including an early aggressive amyloid- (A) pathology in the cortex and hippocampus, regions known to be necessary for learning and memory. We will test our hypothesis that synaptic density represents a key source of vulnerability to AD pathology in females as compared to males. Three distinct Aims will test this hypothesis. First, Aim 1 will evaluate the temporal progression of behavioral decrements in 5xFAD (male/female) mice as well as wild type (WT) mice from 4 through 24 mo of age. In addition, memory processes and also long-term potentiation, a form of synaptic plasticity thought to underlie learning and memory, will be assessed at the same ages. Second, Aim 2 will use clinically relevant magnetic resonance diffusion tensor imaging (dMRI) to map brain learning and memory circuits, probing the hippocampus and related brain structures for connectivity. Third, Aim 3 will explore the use of positron emission tomography (PET) imaging with an 18F radioligand to probe the synaptic marker, synaptic vesicle glycoprotein 2A (S2VA) in our WT and 5xFAD cohort. Preliminary studies have demonstrated loss of S2VA labeling in human AD patients, but have not explored sex-specific alterations. In sum, this research proposal will define the accelerated sex-specific changes in synaptic connectivity, density and physiological function that underlie the increased vulnerability of females when AD pathology is present. Moreover, we will identify when this vulnerability emerges with the future goal of intervening to either prevent or slow the progression of AD pathology.